CN111000832A - Oral film containing cetylpyridinium chloride - Google Patents
Oral film containing cetylpyridinium chloride Download PDFInfo
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- CN111000832A CN111000832A CN201911357724.0A CN201911357724A CN111000832A CN 111000832 A CN111000832 A CN 111000832A CN 201911357724 A CN201911357724 A CN 201911357724A CN 111000832 A CN111000832 A CN 111000832A
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- cetylpyridinium chloride
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- oral film
- hydroxypropyl cellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
Abstract
The invention discloses a cetylpyridinium chloride-containing oral film agent which is prepared from the following raw material medicines and auxiliary materials in parts by weight: 1.0-5.0 parts of cetylpyridinium chloride, 20.0-40.0 parts of hydroxypropyl cellulose, 20.0-30.0 parts of filling agent, 0.5-1.0 part of xanthan gum, 0.5-2.0 parts of carbomer, 20.0-40.0 parts of plasticizer and 2.0-5.0 parts of saccharin sodium. The oral film agent containing cetylpyridinium chloride of the invention can be conveniently applied to patients with dysphagia, the drug release is stable, the bioavailability and the compliance of the patients are improved, the drug exists in the film agent form, the shelf life of the drug can be prolonged, and the effect of covering the bad taste of the drug is achieved.
Description
Technical Field
The invention relates to a traditional Chinese medicine preparation, in particular to an oral film containing cetylpyridinium chloride.
Background
Cetylpyridinium chloride is a cationic quaternary ammonium compound that acts as a surfactant, inhibiting and killing bacteria primarily by reducing surface tension. The in vitro test result shows that the product has inhibiting and killing effects on various oral pathogenic and non-pathogenic bacteria, including Candida albicans. It can reduce or inhibit the formation of dental plaque, and has effects of keeping oral cavity clean and eliminating oral odor.
At present, the cetylpyridinium chloride preparation on the market at home is mainly gargle, and the gargle is inconvenient to carry due to the large volume. The ciclopirox olamine solid preparation is also on the market at home, but the manufacturers are few, only two tablets are on the market, and mainly the ciclopirox olamine solid preparation needs to solve some technical difficulties to ensure that the compliance of patients and the quality stability of products in clinical application meet the requirements. In the process of developing a cetylpyridinium chloride solid preparation, particularly in the process of developing a cetylpyridinium chloride oral film, the applicant unexpectedly found influencing factors which play a key role in the taste and quality of the cetylpyridinium chloride oral film.
The film agent is a solid preparation prepared from a film forming material and medicinal ingredients, and can be disintegrated and released in an oral cavity within minutes without chewing or water administration. The film agent has the advantages of simple preparation method, convenient carrying, no need of water for taking and chewing, quick effect and high patient compliance, and is particularly suitable for bedridden patients, old people and children patients with dysphagia. Because the sublingual mucosa is rich in vein blood vessels, the medicine is directly absorbed and enters the blood circulation, thereby avoiding the first pass effect of the liver and improving the bioavailability of the medicine.
Disclosure of Invention
Aiming at the prior art, the invention provides an oral film agent containing cetylpyridinium chloride, which can be conveniently applied to patients with dysphagia, has rapid drug release, improves bioavailability and patient compliance, can prolong the shelf life of the drug, and has the problem of content reduction commonly existing in the existing cetylpyridinium chloride preparation.
The invention is realized by the following technical scheme:
an oral film containing cetylpyridinium chloride is prepared from the following raw material medicines and auxiliary materials in parts by weight: 1.0-5.0 parts of cetylpyridinium chloride, 20.0-40.0 parts of hydroxypropyl cellulose, 20.0-30.0 parts of filling agent, 0.5-1.0 part of xanthan gum, 0.5-2.0 parts of carbomer, 20.0-40.0 parts of plasticizer and 2.0-5.0 parts of saccharin sodium.
Preferably, the composition is prepared from the following raw materials and auxiliary materials, by weight, 3.0 parts of cetylpyridinium chloride, 40.0 parts of hydroxypropyl cellulose, 25.0 parts of a filling agent, 1.0 part of xanthan gum, 1.0 part of carbomer, 27.0 parts of a plasticizer and 3.0 parts of saccharin sodium.
The hydroxypropyl cellulose is selected from SSL, SL, L, preferably L. The hydroxypropyl cellulose is used as a carrier for inhibiting the formation of drug crystals, accelerating the release of the drug and covering the unpleasant taste of the drug.
The plasticizer is selected from glycerol and sorbitol, preferably sorbitol.
Preferably, the oral film containing cetylpyridinium chloride has a specification of 2.0cm × 2.5cm, and the content of cetylpyridinium chloride by weight is as follows: 3 g/tablet.
The preparation method of the oral film containing cetylpyridinium chloride comprises the following steps:
(1) preparation of cetylpyridinium chloride solution: placing cetylpyridinium chloride and hydroxypropyl cellulose in a mixing stirrer, adding into purified water, and uniformly stirring to dissolve;
(2) preparing an oral film comprising cetylpyridinium chloride:
1) uniformly dispersing hydroxypropyl cellulose in a 60% ethanol solution at 50 ℃ to obtain a hydroxypropyl cellulose solution; taking xanthan gum and carbomer, and respectively and uniformly dispersing with water to obtain xanthan gum-carbomer solution; dissolving a plasticizer in water to obtain a plasticizer solution; 2) adding the xanthan gum-carbomer solution into the hydroxypropyl cellulose solution while stirring, and continuously stirring at room temperature after the addition is finished to uniformly mix; 3) then, dripping a plasticizer solution, and uniformly stirring to obtain a film forming solution; 4) dissolving saccharin sodium with water to obtain saccharin sodium solution; 5) adding the cetylpyridinium chloride solution and the saccharin sodium solution into the film forming solution, stirring at room temperature to uniformly mix, ultrasonically degassing, and standing to obtain the cetylpyridinium chloride film forming solution; 6) the cetylpyridinium chloride film forming solution is coated on a preheated glass plate, dried at 45 ℃ to obtain the oral film containing cetylpyridinium chloride, and then cut (2.0cm multiplied by 2.5cm), packaged and the like are carried out.
The beneficial technical effects of the invention are as follows: the volatilization of the main medicine in the storage process can be effectively avoided; the long-term stability of the product quality is kept, and the curative effect of the product is ensured; the unpleasant odor or taste of the medicine is covered, and the bioavailability is improved; covering up the bad taste of the medicine.
Drawings
FIG. 1 in vitro dissolution comparison.
Detailed Description
The present invention will be further described with reference to the following examples.
EXAMPLE 1 preparation of oral immediate Release film Agents for Cepirammonium chloride
Preparing oral quick-release film agent containing cetylpyridinium chloride, preparing 100 tablets, wherein each tablet contains 3g of cetylpyridinium chloride, and the dosage of raw materials and auxiliary materials is as follows: cetylpyridinium chloride 3g, hydroxypropyl cellulose 40.0g, corn starch 25.0g, xanthan gum 1.0g, carbomer 1.0g, sorbitol: 27.0g and saccharin sodium 3.0 g.
The preparation method comprises the following steps:
(1) preparation of cetylpyridinium chloride: placing cetylpyridinium chloride in a mixing stirrer, adding purified water, and uniformly stirring to dissolve the cetylpyridinium chloride to obtain a cetylpyridinium chloride solution;
(2) preparing an oral film comprising cetylpyridinium chloride:
1) uniformly dispersing hydroxypropyl cellulose in a 60% ethanol solution at 50 ℃ to obtain a hydroxypropyl cellulose solution; taking xanthan gum and carbomer, and respectively and uniformly dispersing with water to obtain xanthan gum-carbomer solution; dissolving a plasticizer in water to obtain a plasticizer solution;
2) adding the xanthan gum-carbomer solution into the hydroxypropyl cellulose solution while stirring, and continuously stirring at room temperature after the addition is finished to uniformly mix;
3) then, dripping a plasticizer solution, and uniformly stirring to obtain a film forming solution;
4) dissolving saccharin sodium with water to obtain saccharin sodium solution;
5) adding the cetylpyridinium chloride solution and the saccharin sodium solution into the film forming solution, stirring at room temperature to uniformly mix, ultrasonically degassing, and standing to obtain the cetylpyridinium chloride film forming solution;
6) the cetylpyridinium chloride film forming solution is coated on a preheated glass plate, dried at 45 ℃ to obtain the oral film containing cetylpyridinium chloride, and then cut (2.0cm multiplied by 2.5cm), packaged and the like are carried out.
Comparative example 1: preparation of oral film containing cetylpyridinium chloride
100 tablets are prepared, each tablet contains 3g of cetylpyridinium chloride, and the dosage of the raw materials and the auxiliary materials is as follows: 3g of cetylpyridinium chloride, 50.0g of hydroxypropyl methyl cellulose, 15.0g of methyl cellulose, 2.0g of gelatin and 1.0g of saccharin sodium.
The preparation method is the same as the step (2) of example 1.
Comparative example 2: buccal tablet (market products)
Experimental comparison of oral film preparation containing cetylpyridinium chloride (prepared in example 1), oral ordinary film preparation containing cetylpyridinium chloride (prepared in comparative example 1) and purchased commercial product, the dosage form is buccal tablet.
Dissolution test:
the experimental method comprises the following steps: the in vitro dissolution of the examples and the control examples was measured according to the fourth method of the general rules of the four parts of the pharmacopoeia 2015 year edition. Purified water degassed by ultrasound is used as dissolution medium, and the temperature is 37 +/-0.5 ℃. Fixing 2.0 x 2.5cm of film agent in the center of two layers of discs, placing the mesh disc at the lower part of the dissolution cup to be parallel to the rotating surface of the paddle bottom, keeping the distance between the film agent and the rotating surface of the paddle bottom by 25 +/-2 mm, rotating at 50r/min for 5min,10min,15min,20min,30min,45min and 60min, taking 5ml of release liquid, supplementing a blank dissolution medium with the same temperature and the same quantity, filtering by a microporous filter membrane, and taking the subsequent filtrate for ultraviolet measurement;
as a result: as shown in fig. 1, it can be seen from fig. 1 that the film containing cetylpyridinium chloride has a faster dissolution rate than the ordinary film and the commercially available troches.
(II) Observation experiment of Effect of oral mucosal reaction
The experimental method comprises the following steps:
36 rats are selected and randomly divided into an observation group and a control group, and the difference of the relevant indexes of the two groups of rats is not significant (P is more than 0.05).
The control group used a common film agent, and the observation group used the film agent prepared in example 1, 3 times/d. Daily observations recorded the feeding status of rats, changes in oral mucosa, etc.
Finally, grading according to a WHO mucous membrane reaction grade 0-4 standard, and comparing, wherein the grade ① 0 is no symptom and no symptom, the grade ② is congestion, edema and punctate ulcer of oral mucous membranes, the grade ③ is II is congestion, edema and punctate ulcer of oral mucous membranes, the grade ④ is III is congestion, edema and lamellar ulcer of oral mucous membranes, the pain is aggravated and the food intake is influenced, and the grade ⑤ is IV is large-area ulcer and severe pain of oral mucous membranes, the mouth opening is difficult to eat, and the food intake needs parenteral nutrition or enteral nutrition support.
The experimental results are as follows:
the comparison of the time of occurrence of the oral mucosal reaction in the two groups of rats was not statistically significant (P > 0.05). The degree of oral mucosa reaction of the two groups is compared, the observed group is lighter than the control group, and the difference has significant significance (P is less than 0.05), which is shown in table 1.
TABLE 1 comparison of oral mucosal responses in two groups of rats
(III) experiments on the effects of gingivitis and plaque:
the experimental method comprises the following steps:
12 patients with fixed orthodontics accompanied with gingivitis, age 19-29 years, were selected and randomly divided into experimental and control groups. After 8-10 days of scaling, 15, 13, 21, 26, 35, 33, 41 and 46 are selected as index teeth, the plaque index and the gum index of the index teeth are recorded as baseline values, a control group uses a common film agent, and an experimental group uses the example 1. The plaque index, gum index were recorded after 4 weeks, 8 weeks, 12 weeks, respectively. In the aspect of statistical processing, single-factor analysis of variance and a student-Newman-Keuls method are adopted for longitudinal comparison; and (4) performing transverse comparison by adopting a t test, and performing statistics by adopting SPSS10.0 software.
The experimental results are as follows:
1. and (3) transverse comparison: the clinical index measured at 4 weeks was compared to baseline levels, with no significant difference between experimental and control groups (P > 0.05); the plaque indexes are significantly different at 8 weeks (P is less than 0.05), and the gum indexes are significantly different (P is less than 0.01); at 12 weeks, the indexes of the experimental group are lower than those of the control group, and the significant difference exists (P is less than 0.01).
2. And (3) longitudinal comparison: compared with the baseline value, the average values of all indexes measured at 4 weeks, 8 weeks and 12 weeks have no significant difference (P is more than 0.05); compared with the baseline value, the reduction of the plaque index at 4 weeks and 8 weeks is significantly different (P is less than 0.05), and the reduction of the plaque index at 12 weeks is significantly different (P is less than 0.01); compared with the baseline value, the change of the gingival index at 4 weeks is not statistically significant (P is more than 0.05), and the gingival index at 12 weeks is obviously reduced (P is less than 0.01) at 8 weeks, which is shown in Table 2.
TABLE 2 comparison of clinical parameters of control and experimental groups
Note that ＊ P < 0.05 and ＊＊ P < 0.01 are compared in the transverse direction.
Claims (6)
1. An oral film comprising cetylpyridinium chloride, characterized in that: is prepared from the following raw material medicaments and auxiliary materials in part by weight: 1.0-5.0 parts of cetylpyridinium chloride, 20.0-40.0 parts of hydroxypropyl cellulose, 20.0-30.0 parts of filling agent, 0.5-1.0 part of xanthan gum, 0.5-2.0 parts of carbomer, 20.0-40.0 parts of plasticizer and 2.0-5.0 parts of saccharin sodium.
2. An oral film comprising cetylpyridinium chloride according to claim 1, characterized in that: is prepared from the following raw material medicaments and auxiliary materials in part by weight: 3.0 parts of cetylpyridinium chloride, 40.0 parts of hydroxypropyl cellulose, 25.0 parts of filler, 1.0 part of xanthan gum, 1.0 part of carbomer, 27.0 parts of plasticizer and 3.0 parts of saccharin sodium.
3. An oral film comprising cetylpyridinium chloride according to claim 2, characterized in that: the hydroxypropyl cellulose type number is selected from SSL, SL, L.
4. An oral film comprising cetylpyridinium chloride according to claim 2, characterized in that: the plasticizer is selected from glycerol and sorbitol.
5. The method of preparing an oral film comprising cetylpyridinium chloride according to any one of claims 1-4, characterized in that: the method comprises the following steps:
1) preparation of cetylpyridinium chloride: placing cetylpyridinium chloride and hydroxypropyl cellulose in a mixing stirrer, adding into purified water, and uniformly stirring to dissolve;
2) an oral film containing cetylpyridinium chloride was prepared.
6. The method of preparing an oral film comprising cetylpyridinium chloride according to claim 5, characterized in that: step 2) the following steps: the preparation of an oral film comprising cetylpyridinium chloride comprises the following steps:
1) uniformly dispersing hydroxypropyl cellulose in a 60% ethanol solution at 50 ℃ to obtain a hydroxypropyl cellulose solution; taking xanthan gum and carbomer, and respectively and uniformly dispersing with water to obtain xanthan gum-carbomer solution; dissolving a plasticizer in water to obtain a plasticizer solution;
2) adding the xanthan gum-carbomer solution into the hydroxypropyl cellulose solution while stirring, and continuously stirring at room temperature after the addition is finished to uniformly mix;
3) then, dripping a plasticizer solution, and uniformly stirring to obtain a film forming solution;
4) dissolving saccharin sodium with water to obtain saccharin sodium solution;
5) adding the cetylpyridinium chloride solution and the saccharin sodium solution into the film forming solution, stirring at room temperature to uniformly mix, ultrasonically degassing, and standing to obtain the cetylpyridinium chloride film forming solution;
6) and (3) coating the cetylpyridinium chloride film forming solution on a preheated glass plate, and drying at 45 ℃ to obtain the oral film containing cetylpyridinium chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911357724.0A CN111000832A (en) | 2019-12-25 | 2019-12-25 | Oral film containing cetylpyridinium chloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911357724.0A CN111000832A (en) | 2019-12-25 | 2019-12-25 | Oral film containing cetylpyridinium chloride |
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| CN111000832A true CN111000832A (en) | 2020-04-14 |
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| CN201911357724.0A Pending CN111000832A (en) | 2019-12-25 | 2019-12-25 | Oral film containing cetylpyridinium chloride |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105407926A (en) * | 2013-05-31 | 2016-03-16 | 久光制药株式会社 | Oral cavity patch |
| CN109700786A (en) * | 2018-12-28 | 2019-05-03 | 重庆健能医药开发有限公司 | A kind of pelliculae pro cavo oris of the solid dispersions containing mosapride citrate |
-
2019
- 2019-12-25 CN CN201911357724.0A patent/CN111000832A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105407926A (en) * | 2013-05-31 | 2016-03-16 | 久光制药株式会社 | Oral cavity patch |
| CN109700786A (en) * | 2018-12-28 | 2019-05-03 | 重庆健能医药开发有限公司 | A kind of pelliculae pro cavo oris of the solid dispersions containing mosapride citrate |
Non-Patent Citations (1)
| Title |
|---|
| M. FRIEDMAN等: "Inhibition of plaque formation by a sustained release delivery system for cetylpyridinium chloride" * |
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